Dysregulation of lipoprotein metabolism may contribute to the excess atherosclerosis in individuals with the metabolic syndrome. This condition is characterized by multiple defects in lipoprotein metabolism, including increases in triglyceride-rich lipoproteins (TRLs). Insulin resistance and hyperinsulinemia underlie the metabolic syndrome, however it is incompletely understood how insulin regulates TRL metabolism. Moreover, TRLs are associated with increased cardiovascular risk, but the mechanisms by which TRLs affect atherosclerosis are not fully known. FoxOs are insulin-repressible transcription factors that have emerged as key mediators of insulin signaling in liver. We?ve determined that FoxOs regulate TRL metabolism, and in this grant, we will determine the mechanisms of this pathway. We will also investigate the effects of this pathway on atherosclerosis. Our study will rely on lipoprotein turnover in vivo using kinetic studies with radiolabeled tracers, and we will use genetic rescue approaches to test causative mechanisms. We will examine effects of the hepatic FoxO-TRL pathway on atherosclerosis and macrophage dysfunctions. These studies will shed light on key unanswered questions in the pathophysiology of metabolic syndrome-related cardiovascular risk, and may reveal better approaches for therapeutic intervention.